A novel role for synaptic acetylcholinesterase as an apoptotic deoxyribonuclease

In addition to terminating neurotransmission by hydrolyzing acetylcholine, synaptic acetylcholinesterase (AChE(S)) has been found to have a pro-apoptotic role. However, the underlying mechanism has rarely been investigated. Here, we report a nuclear translocation-dependent role for AChE(S) as an apoptotic deoxyribonuclease (DNase). AChE(S) polypeptide binds to and cleaves naked DNA at physiological pH in a Ca(2+)–Mg(2+)-dependent manner. It also cleaves chromosomal DNA both in pre-fixed and in apoptotic cells. In the presence of a pan-caspase inhibitor, the cleavage still occurred after nuclear translocation of AChE(S), implying that AChE(S)-DNase acts in a CAD- and EndoG-independent manner. AChE gene knockout impairs apoptotic DNA cleavage; this impairment is rescued by overexpression of the wild-type but not (aa 32–138)-deleted AChE(S). Furthermore, in comparison with the nuclear-localized wild-type AChE(S), (aa 32–138)-deleted AChE(S) loses the capacity to initiate apoptosis. These observations confirm that AChE(S) mediates apoptosis via its DNase activity.